Method of producing ataraxic, anticonvulsant activity and skeletal muscle relaxation



United States Patent Oil 3,314,852 METHOD OF PRODUCING ATARAXIC, ANTI- CONVULSANT ACTIVITY AND SKELETAL MUSCLE RELAXATION Daniel M. Green and Russell F. Krueger, University City, Mo., assignors to Bristol-Myers Company, a corporation of Delaware NoDrawing. Filed Oct. 4, 1963, Ser. No. 313,791

5 Claims. (Cl. 167-65) Typical examples of muscle relaxants of this type include mephenesin, glyceryl guaiacolate, mephenesin carbamate, meprobamate, etc. These products, however, leave much to be desired in their effectiveness.

It has now been found that, as a general proposition, the effect of the skeletal muscle relaxants and particularly, those which are administrable orally, may be potentiated by the simultaneous administration would seem to be contraindicated.

It is accordingly an object of the present invention to provide an effective method for inducing skeletal muscle relaxation and for potentiating the properties of skeletal muscle relaxants.

It is a an effective method for inducing ataraxia and for potentiating the ability laxants to induce ataraxia.

Still another object of this invention is to provide a method for relieving convulsions and for potentiating the ability of antihistamines or skeletal muscle relaxants to relieve convulsions.

It is also an object of the present invention to provide a method for inducing any combination of effects set forth in the above objects.

Other and more detailed objects will the following description and claims.

Compositions containing certain muscle relaxants and antihistamines have been suggested for use in the prior art as therapeutic agents. Thus, for example, preparations including glyceryl guaiacolate and phenyltoloxamine dihydrogen citrate have been suggested for use in obtainbe apparent from 3,314,852 Patented Apr. 18, 1967 Bee Prior art products of the same general character as those described in the paragraph above have also been characterized as being spasmolytic. This activity, howassociated with smooth muscle, for ex or uterus, and not voluntary the present invention is conample, skeletal muscle with which cerned.

mental facilities or clouding consciousness.

Anticonvulsant is used to describe a drug which is effective in preventing an involuntary violent contraction or series of contractions of the voluntary muscles.

( The ether and ester linkages of the group of compounds compound the usual recommended oral human therapeutic dosage.

TAELE I-Continued Skeletal Muscle Relaxant Chemical Structure Any of a variety of antihistamines may also be used in accordance with the present invention. Aside from antihistamine selected should be orally Burger, A., Publishers, Inc, formula where R Medicinal Chemistry, 2nd ed., N.Y., p. 532, 1960 as of and R are aromatic the general (or heterocyclic aromatic) systems, one of which may or may not be separated from X by a methylene group; X is 0, N, or CH; R is an ethylene group or a Z-carbon fragment of a nitrogen-heterocyclic system. R and R are methyl groups, but a small planar cyclic group such as the pyrrolidino group may be employed for NR R Typical Examples are given in Table II below of antihistamines that can be incorporated in the compositions made use of in the present invention. In addition, there is given for each compound the usual recommended oral human therapeutic dosage.

These compounds fall into several may be described as follows:

generic groups which wherein R R R and R are selected from the group consisting of hydrogen, alkyl, aryl, aralkyl and heterocyclic radicals, or R and R together, or R and R together form a ring structure, and R is a divalent radical such as ethylene.

R N- N-R wherein R and R have the same value ascribed to them above.

a R R i C R -N l 1 wherein R and R have the significance ascribed to them it above, in addition to which an unsaturated bond may be located between R and the asterisked carbon atom.

R 0- NR wherein R and R have the significance ascribed to them above. (5) R1---O-R3-N 1 Wherein R R R and R have the same significance ascribed to them above.

TABLE II Recommended Antihistaminic generic name Chemical Structure Oral Human Therapeutic usage, mg.

' Illa III 111 $113 Tripelenuamiue HCl G-III(|3-([J-ITI.HC1 25-100 H H CH3 7 H 0 II; H H OH: H

l i l l COH Pyrilamincilialeate- CHs-O -C-NO-ON H 25-50 I I C-(J-OH Antihistaminic generic name Chemical Structure cm H Recommended Oral Human Therapeutic D osage, rng.

1 l l l Dmienliydrinate (\JO(T C(I \IH lIggC-N 50 100 I OH:

1&1 III I} (311 Bromodiphenhydramine Br(]3-O-t\l(]l-.IIO1 -50 H H CH:

(111 H III CF11; Doxylaminc Succinate li-o cro-n.oimoi 12-25 II H CH N H O H H H CH3 H l l l l CC--OH Carbinoxamine Maleatc Cl -C'O-CGN H 2% l l l Co-o1r H H CH3 l H H O Plienyltoloxamine Dihydrogen Citrate, or

Hydrochloride.

In the present invention any antihistamine described above or combinations thereof may be used in conjunction with any skeletal muscle relaxant or combinations thereof, also defined above. In addition, where desired, other pharmacologically active materials may also be introduced. Among these may be mentioned analgesics, diuretics, hypotensives, etc. Typical examples of these materials include aspirin, salicylamide, phenacetin, acetaminophen, theophylline, 7-B-hydroxypropyl theophylline, theobromine, chlorothiazide, hydroflumethiazide, mannitol, ethyl alcohol, ammonium chloride.

The enhanced pharmacological activity of the compositions employed in this invention is evident over a fairly wide range of proportions of the two principal ingredients. The relative proportions of the ingredients utilized will be dependent on the particular skeletal muscle relaxant utilized and the specific antihistaminic that is selected. These are related to the recommended oral human therapeutic dosages of these materials as follows:

1. Skeletal muscle relaxants: from one-half the minimum dosage given in the range of recommended oral human dosage through the dosage range given (Table I).

2. Antihistaminies: from one-half the minimum dosage given in the range of recommended oral human dosage through twice the dosage range given (Table II).

II II 0113 H01 and other salts However, in general, the range of ratios of parts of skeletal muscle relaxant to antihistamine may vary from 4 to 500 parts of skeletal muscle relaxant to one part of antihistamine by weight, and preferably, from 4 to 32 parts of muscle relaxant per part of antihistamine. Most desirably, about 4 to 8 parts by weight of the former per part of the latter is used.

The unit dosage that is suitable for human use may also vary considerably depending on the degree of effect desired, the age of the patient, the muscle relaxant employed or the antihistamine utilized. In general, the oral human dosage will vary from about 13.5 mg. of the combined principal active components to about 3200 mg. in which the skeletal muscle relaxant and the antihistamine will be included in the ratios outlined above.

The active ingredients of the composition can be administered in unit dosage form without diluents or with the conventional pharmaceutical carriers. Each unit dosage form of the composition containing conventional carriers can have from about 5% to about 95% and preferably, from about 10% to of the combination of muscle relaxant and antihistamine by weight of the entire unit dosage with the remainder comprising conventional pharmaceutical carriers. By the term pharmaceutical carrier we intend to include materials which are conventionally used with unit dosages and include fillers, diluents,

ventional pharmaceutical carriers to produce their phar- Oral administration by the use of solid tablets, pills glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate and talc. Illustrative of disintegrating agents there can be mentioned: corn starch, keratin, and potato starch.

The antihistamine is preferably used in the form of its acid addition salts. These can be produced by the conphoric acids (e.g., is dihydrogen citrate).

The invention is illustrated by the following examples dosages be limited by any of the proportions, amounts, types of carriers, or dosage units set forth therein.

EXAMPLE 1 A suitable formulation of tablets to be employed as muscle relaxant can have the following composition per tablet:

Weight in milligrams (1) Glyceryl guaiacolate 200.0 (2) Aspirin 300.0 (3) Phenyltoloxamine dihydrogen citrate 12.5 (4) Corn starch 51.0 (5) Talc 6.0 (6) Gelatin 2.0

EXAMPLE 2 A suitable dosage, particularly for muscle relaxation, can contain the following ingredients in a water-soluble capsule:

Weight in milligrams (1) Glyceryl guaiacolate 200.0 (2) Phenyltoloxamine dihydrogen citrate 12.5 (3) Salicylamide 300.0

EXAMPLE 3 Another suitable dosage can contain the following ingredients in a tablet with binding and disintegrating agents:

Weight in milligrams EXAMPLE 4 Another suitable dosage can contain 200 mg. of glyceryl guaiaeolate and 40 mg. of phenyltoloxamine dihydrogen citrate.

EXAMPLE 5 Another suitable capsule dosage form can contain 400 mg. of glyceryl guaia-colate with any one of the following antihistamines Weight in milligrams (1) Chloropheniramine maleate 8 (2) Phenindamine tartrate 50 (3) Pyrilamine maleate 50 (4) Tripelennamine HCl 25 1 4 EXAMPLE 6 Another suitable dosage can be 50 mg. phenyltoloxamine dihydrogen citrate with any one of the following muscle relaxants:

Weight in milligrams (1) Carisoprodol 200 (2) Meprobamate 200 (3) Mephenesin (4) Methocarbamol 500 EXAMPLE 7 Another suitable dosage in a tablet can have the follow ing ingredients:

Weight in milligrams (l) Glyceryl guaiacolate 200 (2) Phenyltoloxamine dihydrogen citrate 25 (3) Acetaminophen 300 Brit. J. PharmacoL, 14: 415, 1959.

The animals used in these tests are sensitive to auditory stimuli to which they are subjected. They react to the stimulus by running, jumping, circling or going into conministered separately, the carried out:

Male albino mice weighing 14 to 30 gm. ('audiogenic strain, Research Animals Incorporated, Pittsburgh, Pa.) were used. They were maintained on a standard diet at a room temperature between 23 and 26 degrees C. (74 and 79 degrees F.) and allowed food and water ad libitum except during test time. Twenty-five mice were used for each dose studied.

On the first day of study the mice were given 0.15% hydroxyethylcellulose (HEC) in distilled water, 0.5 ml./

gm. mouse, intragastrically, and the drugs were given on the following day in 0.15 HEC in distilled water, 0.5 ml./20 gm. mouse, intragastrically. Thus, each mouse served as its own control.

Fifteen minutes after administration of either the BBC the t the following: running, and oatalepsy. Each of score of one point.

jumping, circling, convulsing, theserresponses was given a The differences between the total The PD (fifty percent protective dose) was estimated Protection against electroshock seizures in mice and according to the method of Litchfield and Wilcoxon (J. rats has been employed by numerous investigators as a Pharmacol. Exp. Therap., 96:99, 1949). means of selecting and evaluating drugs useful for the Table III below summarizes the results of these tests treatment of certain disorders in man, including drugs using a combination of glyceryl guaiacolate and phenyl- 5 with central nervous system depressant action, anticontoloxamine dihydrogen citrate in various ratios. In each vulsant, psychopharmacologic and muscle relaxant propoategory of ratio studied, it can be seen that the actual erties. Among some of the previous reports of such protection afforded by the combination of the drugs was are those in mice (Chen, G., B. Bohner and E. R. Ensor: far greater than the arithmetic sum of the effects of the Proc. Soc. Exper. Biol. and Med, 87: 334, 1954; Chen, individual drugs. This clearly illustrates the potentiating 10 G. and B. Bohner: Proc. Soc. Exper. Biol. and Med., effect which is characteristic of the present invention. 106: 632, 1961; Pink, G. B. and E. A. Swinyard: I. Am. TABLE III.-GONTRIBUTION on GLYCERYL GUAIACOLATE AND PHENYLTOLOXAMINE DII'IYDROGEN CIIRA'IE IN RATIOS OF 4 TO 1, 8 TO 1,16 TO 1 AND 32 TO 1, TO THE THEORETICAL AND THE ACTUAL PROTECTION OF MICE FROM AUDIO GENIC SEIZURES, AT THE IDsn DOSAGE 4 to 1 Ratio 8 to 1 Ratio 16 to 1 Ratio 32 to 1 Ratio f Active Ingredients Mouse Percent Mouse Percent Mouse Percent Mouse Percent Dose Protection Dose Protection Dose Protection Dose Protection s/ks) a/ s) s/kg) (mg/kg.)

M Glyeeryl guaiacolate 280. 0 35. 8 435 4.3. 5 Phenyltoloxarnine dihydrogen citrate 70 0 0.0 13. (i 0.0 Theoretical additive amount of protection 35. 8 43. 5 Actual amount of protection from combination 50.0 50.0

1 Determined from dose-response curves. 1 Estimated from tabular data only.

Table IV below summarizes the results of a series of Pharm. Assoc., Sci. Ed, 49: 510, 1960; Gesler, R. M., tests similar to those summarized in Table III. In this C. E. Lints and E. A. Swinyard: Tox. and Appl. Pharcase, however, glyceryl guaiacolate is used in conjunction maeo1., 3: 107, 1961; Mitchell, C. L. and H. H. Keasling: with a series of different antihistamines. The results oh- J. Pharmacol. Exper. Therap, 128: 79, 1960; Weiss, B.

tained are similar. In each case the actual protection 30 and C. G. T. Ewing: Am. I. Pharnr, 131: 307, 1959;

is far in excess of the expected protection calculated on Witkm, L. 13., P. Spitaletta, F. Galdi and E. OKeefe: Tox. the basis of the individual effects. and Appl. PharmaooL, 2: 264, 1960; Truitt, E. B. Jr. and

TABLE IV.TIIEORETICAL SUM OF PROTECTION AFFORDED BY COMBINATIONS OF GLYCERYL GUAIACOLATE AND THE ANTII-IISTAMINIC CI-ILORCYCLIZINE HYDROCHLORIDE, CIILORPIIENIRAMINE MALEATE, PHENINDAMINE TARTRATE, TRIIELENNAMINE HYDROCHLORIDE AND PYRILAMINE MALEATE, IN VARIOUS RATIOS, AS COM- PARED WITH THE ACTUAL PROTECTION OF MICE FROM AUDIO GENIC SEIZUIIES 8 to 1 ratio 16 to 1 ratio 8 to 1 ratio Active Ingredients Percent Mouse Percent Mouse Percent Percent Protec- Dose, Protec- Dose, Protec- Protoction lug/kg. tion lug/kg. tion fl Glyceryl guiacolate..- Chloreyelizine hydroe oride. Glyeeryl guaiaeolate Chlorphenirarnine maleate Tripelennainine hydr Glyceryl guaiacolate.

Pyrilamine maleate Theoretical sum of protection Actual amount of protection from com nation 1 Determined from the dose response curves. 1 Increase in audiogenic seizure.

Table V summarizes the result of a series of tests similar I. M. Little: J. Pharmacol. Exper. Therap, 122: 239, to those summarized in Tables .111 and IV. In this case, 1958) in rats (Swinyard, E. A.: J. Am. Pharm. Assoc, however, the same antihistamine, i.e. phenyltoloxamine, 55 Sci. Ed, 38: 201, 1949; Toman, I. E. P., E. A. Swinyard is used With a series of difierent skeletal muscle relaxants. and L. S. Goodman: J. Neurophysiol., 9: 231, 1946) and The results are similar to those shown in Tables III and in both mice and rats (Chen, G. and C. R. Ensor'. Arch. IV. 1 Neurol. and Psychiat, 63: 56, 1950; Gray, W. D., C. E.

TABLE V.TIIEORETICAL SUM OF PROTECTION AEFO REED BY COMBINATIONS OF THE MUSCLE RELAXANTS, CARI- SOIRODOL, MEPHENESIN, MEPROBAMATE AND METI'IOCARBAMOL, AND THE ANTIIIISTAMINIC II'IENYLTOLOX- ANIZINJE DIHYDROGEN CITRATE, AS COMPATED WITH THE ACTUAL PROTECTION OF MICE FROM AUDIOGENIC SE Z RES 4 to 1 Ratio 4 to 1 Ratio 4 to 1 Ratio Active Ingredients Mouse Percent Mouse Percent Mouse Percent Percent Dose Protection Dose Protection Dose Protection Dose Protection a/ s) (ma/ s/ s) (me/ c.)

Carisoprodol 'Phenyltoloxamine dihydrogon citrate Mephenesin Phenyltoloxamine dihydrogen eitrat Meprobamate 200 Phenyltoloxamine dihydrogen eitra Methocarbamol 8 Phenylto loxarnine dihydrogen citrate .g 6

Theoretical sum of protection Actual amount of protection from combinatiom.

17 Rauh, A. C. Osterberg and L. M. Lipchuck: J. Pharmacol. Exper. Therap, 124: 149, 1958; Swinyard, E. A., W. C. Brown and L. S. Goodman: J. Pharmacol. Exper. Therap, 106: 319, 1952).

To test the skeletal mouse ears by clips and was delivered up to a maximum of seconds duration.

The mouse is subjected to the supramaximal current fifteen minutes after intragastric administration of either the drug with 0.15% hydroxyethylcellulose (HEC) in distilled water, 0.5 ml./ 'gm. mouse, or of HEC alone, to control animals.

A decrease in the number of mice having the vhindleg tonic-extensor component of the seizure, as compared with the control group, was used as a measure of protective activity. The PD (fifty percent protective dose) was estimated according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exper. Therap., 9 6: 99, 1949).

against supramaximal electroshock seizures in mice, and over the same broad range of ratios, as was shown in audiogenic seizure studies.

TABLE VL-CONTRIBUTION RATIOS OF 4 TO OF GLYCE RYL GUAIACOLATE AND PHENYLTOLOXAMINE 1. 8 TO 1 AND 16 TO 1 TO THE THEORETICAL AND 18 of glyceryl guaiaoolate, methocarbamoyl', mephenesin, mephenesin .carbamate, carisoprodol, emylcamate, meprobamate, hydroxyphenarnate, styramate, chlorzoxazoue, zoxazolamine, hydroxyzine and phenaglycodol; and said HCl, metaphenilene HCl, methapyrilene HCl, chlorothen citrate, thenyldiamine HCl, meclizine hydrochloride, cyclizine hydrochloride, chlorcyclizine, promethazine hydrochloride, pyrathiazine hydrochloride, pheniramine maleate, chlorpheniramine maleate, brompheniramine maleate [d-isomer], triprolidone hydrochloride, pyrrobutamine phosphate, diphenylpyraline hydrochloride, phenindamine tartrate, diphenhydramine, dimenhydrinate, bromodiphenhydramine, doxylamine succinate, amine maleate, phenyltoloxamine dihydrogen citrate and phenyltoloxamine dihydrogen hydrochloride.

2. A method according to claim 1 wherein the total dosages of from 13.5 to 3200 mg. of the combination of muscle relaxant and antihistamine is administered.

phenyltoloxamine dihydrogen citrate.

4. A method according to claim 2 wherein the muscle relaxant is glyceryl guaiaoolate and the antihistamine is chlorcyclizine hydrochloride.

5. A method according to claim 2 wherein the muscle relaxant is glyceryl guaiacolate and the antihistamine is chlorpheniramine maleate.

6. A method according to claim 2 wherein the muscle relaxant is glyceryl guaiacolate and the antihistamine is phenindamine tartrate.

7. A method according to claim 2 wherein the muscle relaxant is glyceryl guaiacolate and the antihistamine'is tripelennamine hydrochloride.

8. A method according to claim 2 wherein the muscle relaxant is glyceryl guaiacolate and the antihistamine is pyrilamine maleate.

9. A method according to claim 2 wherein the muscle relaxant is carisoprodol and the antihistamine is phenyltoloxamine dihydrogen citrate.

10. A method according to claim 2 wherein the muscle DIHYDRO GEN CITRATE IN THE ACTUAL PROTECTION OF MICE FROM SUPRA- MAXIMAL ELECTROSHOOK SEIZUliES, AT THE PDm 1 DOSE.

4 to 1 Ratio 8 to 1 Ratio 16 to 1 Ratio Active In redients g Mouse Dose Percent Mouse Dose Percent Mouse Dose Percent (mg/kg.) Protection (mg/kg.) Protection (mg/kg.) Protection M x Glyceryl guaiacolate 397. 0 2 1. 4 474. 0 l0. 5 500 16. 2 Phenyltoioxamine dihydrogen citrate.-. 99. 25 0.0 59. 25 0.0 31. 25 0.0 Theoretical additive amount of protectio 1. 4 10.5 16.2 Actual amount of protection from eombina on (PD D) 50.0 50.0 50.0

1 Fifty percent protective dose (PD) as determined from dose-response CUIVCS.

Although the invention has been described with reference to specific forms thereof, it will be understood that many changes and modifications may be made without departing from the spirit of this invention.

What is claimed is:

1. A method of (a) inducing relaxation of at least one of skeletal muscle in animals suffering from involuntary tamine or a pharmaceuti-cally acceptable non-toxic acid per part of antihistamine; said muscle relaxant being selected from the group consisting 2 Determined from dose-response curves. 1 Estimated from tabular data only.

relaxant is mephenesin and the antihistamine is phenyltoloxamine dihydrogen citrate.

11. A method according to claim 2 wherein the muscle relaxant is meprobamate and the antihistamine is phenyltoloxamine dihydrogen citrate.

12. A method according to claim 2 wherein the muscle relaxant is methocarbam-ol and the antihistamine is phenyltoloxamine dihydrogen citrate.

13. A method of relieving convulsions in animals which comprises orally administering to said animals a composition containing glyceryl guaiacolate and a pharmaceutically acceptable non-toxic acid addition salt of phenylt-oloxamine, the said composition containing from about 4 to about 20 parts of glyceryl guaiacolate per part of the phenyltoloxamine salt by weight.

14. A method according to claim 13 wherein the 19 phenyltoloxamine salt is phenyltoloxamine dihydrogen citrate.

15. A method according to claim 13 wherein said composition contains between about 212.5 to 3100 mg. of the combination of glyceryl guaiacolate and said addition salt of phenyltoloxamine.

References Cited by the Examiner UNITED STATES PATENTS 2,770,649 11/1956 Murphey "167-65 2,863,865 12/1958 Aspergren "167-65 2,874,190 2/1959 Goldberg 167-65 2,895,960 7/1-959 Lunsford 167-65 2,928,767 3/1960 601651611 16765 2,992,222 7/1960 Sommers 167-65 FOREIGN PATENTS 608,814 11/1960 Canada.

OTHER REFERENCES The Antihistamines-Feinberg et al. (1950) pp. 180- 183.

Barsa, Am. I. Psych, vol. 17, No. 5, pp. 448-449.

Cronk, New York State J. Med., vol. 55, pp. 1465- 1467, May 1955.

Di Mascio, Am. J. Psychiatry, 317, October 1958.

Kopmann, Proc. Soc. Exptl., Biol. Med, vol. 97, No. 1,

Merck Index, 7th ed., 1960, pp. 454, 500, 546, 646, 647, 667, 680, 772, 791, 967 and 987.

Robinson, 1., Pharm. Assoc., Sci. Ed., September 1957, vol. 46, No.9, p. 556.

Tice, Am. J. Pharm, p. 398.

Wilson, Am. Drug 353,596,597.

vol. 115, No.4, pp. 301- vol. 128, No. 12, December 1956,

Index, Lippincott Co., 1962, pp.

SAM ROSEN, Primary Examiner.

P. L. SABATINE, M. I. COHEN, Assistant Examiner,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,314,852 April 18, 1967 Daniel M.! Green et al.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column l7 line 64, cancel "of at least one"; same line 64, after of"; first occurrence, insert at least one of Signed and sealed this 5th day of August 1969,

(SEAL) Attest:

Edward M. Fletcher, Jr.

Attesting Officer Commissioner of Patents WILLIAM E. SCHUYLER, JR. 

1. A METHOD OF (A) INDUCING RELAXATION OF AT LEAST ONE OF SKELETAL MUSCLE IN ANIMALS SUFFERING FROM INVOLUNTARY CONTRACTIONS OF SKELETAL MUSCLE; AND (B) RELIEVING CONVULSIONS IN AN ANIMAL SUFFERING FROM THE SAME; AND (C) INDUCING ATARAXIA IN AN ANIMAL SUFFERING FROM NERVOUS TENSION; WHICH COMPRISES ORALLY ADMINISTERING TO SAID ANIMAL A THERAPEUTICALLY EFFECTIVE QUANTITY OF THE COMBINATION OF A SKELETAL MUSCLE RELAXANT AND AN ANTIHISTAMINE OR A PAHARMACEUTICALLY ACCEPTABLE NON-TOXIC ACID ADDITION SALT THEREOF IN THE RATIO OF 4 TO 32 PARTS OF SKELETAL MUSCLE RELAXANT PER PART OF ANTIHISTAMINE; SAID MUSCLE RELAXANT BEING SELECTED FROM THE GROUP CONSISTING OF GLYCERYL GUAIACOLATE, METHOCARBAMOYL, MEPHENESIN, MEPHENESIN CARBAMATE, CARIOPRODOL, EMYLCAMATE, MEPROBAMATE, HYDROXYPHENAMATE, STYRAMATE, CHLORZOXAZONE, ZOXAZOLAMINE, HYDROXYZINE AND PHENAGLYCODOL;L AND SAID ANTIHISTAMINE BEING SELECTED FROM THE GROUP CONSISTING OF TRIPELENNAMINE HCL, PYRILAMINE MALEATE, THONZYLAMINE HCL, METAPHENILENE HCL, METHJAPYRILENE HCL, CHLOROTHEN CITRATE, THENYLDIAMINE HCL, MECLIZINE HYDROCHLORIDE, CYCLIZINE HYDROCHLORIDE, CLORCYCLIZINE, PROMETHAZINE HYDROCHLORIDE, PYRATHIAZINE HYDROCHLORIDE, PHENIRAMINE MALEATE, CHLORPHENIRAMINE MALEATE, BROMMPHENIRAMINE MALEATE (D-ISOMER), TRIPROLIDONE HYDROCHLORIDE, PYRROBUTAMINE PHOSPHATE, DIPHENYLPYRALINE HYDROCHLORIDE, PHENINDAMINE TARTRATE, DIPHENHYDRAMINE, DIMENHYDRINATE, BROMODIPHENHYDRAMINE, DOXYLAMINE SUCCINATE, CARBINOXAMINE MALEATE, PHENYLLTOLOXAMINE DIHYDROGEN CITRATE AND PHENYLTOLOXAMINE DIHYDROGEN HYDROCHLORIDE. 